1992 Fighting long-held beliefs in kidney disease

Fighting long-held beliefs in kidney disease

Barry Freedman, MD, has a habit of talking at breakneck speed in his native Brooklyn accent, dropping in the occasional native invective, his voice rising in tone to accentuate key points. Sharing the story of his life’s work at Wake Forest Baptist, Freedman can’t help but occasionally jab at his critics. They tried for nearly a generation to tear down his theories on kidney failure in African-Americans—the central point of which is that genetic or inherited factors account for much of the racial differences in non-diabetic kidney disease.

But Freedman’s belief was finally proven true in 2010 when three teams of scientists announced they had identified a major gene, APOL1, that was the source of kidney failure in many African-Americans. The scientists were based at Wake Forest Baptist, at Beth Israel Deaconess Medical Center in Massachusetts and at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

“The bottom line is that we took something that was as established as the sky is blue…that hypertension commonly caused kidneys to fail in African-Americans and led to the higher rates of dialysis in this population group. And we stated this was completely wrong,” Freedman said. “We told everyone the story was backward.”

Indeed, it is the APOL1 gene that first brings on kidney disease, which in turn causes high blood pressure. No matter how aggressively African-Americans were treated for high blood pressure or with which medications, those with two risk variants in their APOL1 gene were more likely to develop kidney failure.

Although Freedman cited 1992 as a starting point because it was when his first paper was published suggesting that there was a “kidney failure gene,” his premise was rooted in his time as a medical student in New York. He recalled a paper in the New England Journal of Medicine in which AIDS patients from New York City were reported to develop kidney failure, prompting a rebuttal by physicians in San Francisco saying kidney disease wasn’t observed there. “The patients with AIDS in San Francisco were more often white; while those in New York were most often black. Blacks develop kidney disease from AIDS or HIV infection nearly 50 times more often than whites. So I’ve always paid attention to the excess risk of kidney disease in blacks compared to whites.”

After coming to Wake Forest Baptist as a fellow in 1987 and joining the staff as a nephrologist in 1989, Freedman began to see an interesting phenomenon in the clinic. When he told white patients they needed to start dialysis, “tears would flow because they knew so little about kidney disease and were afraid.” But when it came time to give the same diagnosis to African-American patients, they’d say “’Dr. Freedman, can you put me on the Monday-Wednesday-Friday dialysis shift at 8 a.m.?’

“I’d ask, ‘How do you even know about the Monday-Wednesday-Friday dialysis shift?’ They would answer, ‘Doctor, my brother, my cousin, my uncle, my dad, they’re all there. If you put me there too, we could all drive in together.’”

In case after case involving African-American patients, Freedman said, many accepted that for them, kidney disease was a family disease. So Freedman began to collect DNA samples and apply for grants to the National Institutes of Health. He now has one of the largest single-center DNA collections in African-Americans with kidney disease. The database today is more than 18,000 samples strong and growing.

For his early efforts, Freedman was often ostracized, a victim of the common wisdom of the day that kidney failure in African-Americans was largely linked to high blood pressure. Scientists reviewing his grant proposals frequently rejected them; commentaries on papers he published based on his documenting of family histories excoriated him.

The issue of race and disease became a key point in the struggle to prove his theory.

“First, I was ridiculed by kidney and hypertension specialists, later by geneticists who said there’s no variant in a gene that’s present in one population, but not in others. In 2005, the New England Journal of Medicine published a major paper on race and genetics. The authors wrote ‘Those who claim that gene variants present in one race contribute to differences in common diseases were biased.’ Amazingly, they referenced my paper about kidney disease in blacks, suggesting that I was the one who was biased.”

“We had people trying to block our efforts in the hypertension and genetics communities for years. However, we persevered and kept fighting to help our patients.”

Then, a new genetics technique called admixture mapping was developed. This allowed identification of genetic variants involved in human disease by breaking down the unique genomic structure of populations of mixed heritage, such as African-Americans. This technique allowed Freedman and his colleagues to identify the variants in the APOL1 gene that were accounting for kidney problems in many African-Americans. The definitive work identifying that gene was published in 2010. Freedman said he never had personal doubts about his work, rooted as it was in his patients. “When I see patients in the clinic—that is my laboratory—that is where my ideas develop.”

Twenty years after first positing his theory, Freedman said he knows his work is hardly done. Research barrels along on two fronts — finding potential solutions to kidney disease now that this major gene has been identified, and finding genes causing other diseases.

The cure for kidney failure in African-Americans lies in the near future, and Freedman said two new studies at Wake Forest Baptist are under way to solve the problem. In the laboratory, work is under way to learn more about how the gene injures kidney cells. “Once we understand that, it may lead to new treatments.” A second study searches for secondary triggers to the APOL1 gene. If a virus other than HIV is a trigger for kidney disease, vaccines could be developed to try to prevent it.

Freedman grows even more animated talking about how he and colleagues at Wake Forest Baptist are using the new genetic techniques to find heart disease and osteoporosis genes in African-American and white populations. The idea came about because African-Americans have a lower risk of heart disease and osteoporosis than whites—once differences in access to health care and socioeconomic factors are taken into account. In fact, Freedman said, “osteoporosis is more commonly a disease of white and Asian women.”

Consuming more calcium through diet and having higher vitamin D levels is supposed to protect from bone disease. But even though black women generally consume less dietary calcium and have lower vitamin D levels than white women, they have far fewer instances of osteoporosis. That suggests that genes may contribute to racial differences in bone disease. “We recently showed that vitamin D-associated protection from bone disease differs in black and white populations,” Freedman said. “We also found a link between the calcium content in bones and calcium build-up in heart arteries or atherosclerosis.

“We think the same genes may regulate both calcium deposition in the heart arteries and bone calcium content/osteoporosis. We’re using new genetic strategies to detect both heart attack and osteoporosis genes.”

Meanwhile, related discoveries continue. A recent paper by Freedman’s research team showed that people who received a kidney transplant from a donor with two APOL1 kidney risk variants didn’t maintain kidney function for as long, whether they were white or African-American. “We’ve reversed many long-held tenets in the field of kidney disease. Now we are showing that you can predict how well a transplanted kidney will function based on the donor’s genetic make-up. These advances will help transplant medicine, as well.”

Today, Freedman is the John H. Felts III, MD Distinguished Professor of Internal Medicine and chief of the nephrology section. His division not only has consistently been nationally ranked by U.S. News & World Report, but in 2012 was ranked 12th nationally, the highest ever for a Wake Forest Baptist specialty.

Being proven correct is rewarding, but Freedman said he didn’t let the naysayers bother him over the years.

“I’ve always believed in the power of genes. I never had doubt for one second,” he said before adding with a laugh, “I’m just glad that I lived long enough to see the kidney disease gene found…the search nearly killed me!”

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